The present invention relates to a medical composition containing a nitroetheneamine derivative or a salt thereof as an active constituent.
The present invention relates to a medical composition containing a nitroetheneamine derivative or a salt thereof as an active constituent, which has excellent matrix metalloproteinase inhibitory activities and which is useful as an angiogenesis inhibitor, an anticancer agent, a tumor cell infiltration inhibitor or a tumor metastasis inhibitor useful for treatment or prevention of cancer or inflammatory diseases, or as a therapeutic or preventive agent for an articular disease such as chronic articular rheumatism, osteoarthritis or rheumatoid arthritis, or as a therapeutic or preventive agent for various diseases such as gingivitis, glomerular nephritis, interstitial nephritis, encephalomyelitis, arterial sclerosis, cirrhosis, restenosis, diabetic retinopathy, neovascular glaucoma, corneal ulcer, epidermolysis bullosa, herniated disk, a bone resorption such as osteoporosis, multiple sclerosis, bronchial asthma, Alzheimer""s disease or an autoimmune disorder (such as Crohn""s disease or Sjxc3x6gren""s syndrome). Further, some of the nitroetheneamine derivatives and their salts which are active constituents of such medical compositions, are novel compounds, and the present invention relates also to such novel compounds.
Connective tissues of higher organisms are constituted by extracellular matrices. Extracellular matrices maintain homeostatis of biodynamic functions by repeating new formation and degradation (reassembly) depending upon the functions or morphological features of the particular tissues. Matrix metalloproteinases (MMP) are primary enzymes involved in the decomposition of extracellular matrices and characterized in that they have a bivalent zinc ion at the active center. Presence of about 20 types of MMP has been confirmed up to now including a secreted-type and a membrane-anchored-type, and the physiological functions and in-vivo distributions of the respective molecules are being made clear. MMP in a normal living body acts at a site where restructuring of tissues is required, for example, at a fetal development or for wound healing. However, in order to prevent destruction of extracellular matrices more than necessary, a strict regulation mechanism (regulation of expression or feedback regulation) is functioning. Namely, MMP is usually secreted as an inactive substance by external stimulation and then converted to an active substance by various proteases. On the other hand, the decomposition activities by MMP are controlled by TIMP (tissue inhibitor of metalloproteinase) as its endogenous inhibitor. However, if some abnormality occurs in the above control mechanism, and MMP becomes excessive, various tissue diseases will be induced.
For example, {circle around (1)} with respect to MMP-9 (gelatinase B/92 kDa type IV collagenase) having a strong decomposition activity against type IV collagen which is the main constituting component of a basement membrane, no substantial expression is usually observed in human normal tissues. On the other hand, its over expression has been observed in many epithelial cancer cells and hematopoletic cancer cells including cells of breast cancer and lung cancer. {circle around (2)} In carcinoma of the colon and rectum, a positive correlation has been observed between the expression level of MMP-9 and the metastatic nature (M. Nakajima et al, Journal of National Cancer Institute, Vol. 82, 1890, (1990)). {circle around (3)} It has also been experimentally shown with respect to various cancer cells that the metastatic potential or infiltrating potential of cancer cells in which MMP-9 or MMP-2 (gelatinase A/72 kDa type IV collagenase) is highly expressed, is advanced as compared with cells in which such expression is low (D. R. Welch et al, Proceedings of the National Academy of Sciences of the United States of America, Vol. 87, 7687, (1990), S. Yamagata et al, Biochemical and Biophysical Research Communication, Vol. 151, 186-162 (1988)). {circle around (4)} With respect to MMP-13 (collagenase 3), no expression has been observed in normal cells, but its high expression has been observed in breast cancer cells (J. M. Freiji, M. Nakajima et al, Journal of Biological Chemistry, Vol. 269, 16766-76773, (1994)).
Thus, highly malignant metastatic cancer cells have abnormal motility, adhesion and tissue invasive potential in addition to abnormal growth nature inherent to neoplasm, and as one of the background factors, excess production of MMP is involved.
Further, it is already known that {circle around (1)} MMP is involved in capillary-like tube formation of cultured vascular endothelial cells (R. Montesano et al, Cell, Vol. 42, 469-477, (1985)), {circle around (2)} MMP acts as one of angiogenesis factors to promote tumor growth (T. Itoh et al, Cancer Research, Vol. 58, 1048-1051, (1998) ), or {circle around (3)} with melanoma cells wherein TIMP-2 is excessively expressed, the tissue-infiltration ability or the angiogenesis inducibility decreases (P. Valente et al, International Journal of Cancer, Vol. 75, 246-253 (1998)).
On the other hand, if inflammatory cytokine is induced by some factor at the joint region, and MMP-1 (interstitial collagenase) or MMP-3 (Stromelysin 1) from synovial cells is excessively produced and stored in a large amount in the joint fluid, it acts on the joint cartilage to destroy the cartilage matrix, thus leading to so-called articular diseases represented by symptoms such as pain, regulation of variable joint region or deformations.
Further, it is known that in a coronary disease, MMP will promote migration of smooth muscle cells from the vascular wall to the intima and will promote formation of atherosclerotic plaques, and further that it is involved in reconstruction after angioplasty in the anginal therapy (D. C. Celentano et al, Journal of Clinical Pharmacology, Vol. 37, 991-1000, (1997)).
Further, in gingivitis, an increase in the production of MMP-1 (interstitial collagenase) is observed.
Thus, MMP is responsible for a wide range of physiological functions in a living body, and its overproduction will upset the homeostasis of the living body and will induce a new disease or aggravation of pathology. Accordingly, a MMP inhibitor is considered to be useful as an angiogenesis inhibitor, an anticancer agent, a tumor cell infiltration inhibitor or a tumor metastasis inhibitor, to be used for treatment or prevention of cancer or inflammatory diseases; a therapeutic or preventive agent for an articular disease such as chronic articular rheumatism, osteoarthritis or rheumatoid arthritis; or as a therapeutic or preventive agent for various diseases such as gingivitis, glomerular nephritis, interstitial nephritis, encephalomyelitis, arterial sclerosis, cirrhosis, restenosis, diabetic retinopathy, neovascular glaucoma, corneal ulcer, epidermolysis bullosa, herniated disk, a bone resorption such as osteoporosis, multiple sclerosis, bronchial asthma, Alzheimer""s disease or an autoimmune disorder (such as Crohn""s disease or Sjxc3x6gren""s syndrome).
Heretofore, many compounds having MMP inhibition activities have been reported (R. A. Nigel et al, Current Opinion on Therapeutic Patents, Vol. 4, 7-16, (1994), R. P. Beckett et al, Drug Discovery Today, Vol. 1, 16-26, (1996)). However, most of them are peptide derivatives designed based on the amino acid sequence of the enzymatic cleavage site in the collagen molecule constituting the substrate of MMP, including, for example, hydroxamic acid type compounds; thiol type compounds; carboxylic acid type compounds; phosphonate type compounds; and phosphonate type compounds. Among them, with respect to some compounds including hydroxamic acid derivatives, clinical trial have been carried out on diseases such as cancer and arthritis.
It is generally known that a MMP inhibitor having a peptide in the basic structure has a low oral absorbance, and particularly, a hydroxamic acid type MMP inhibitor is considered to be poor in the stability in plasma, and a carboxylic acid type MMP inhibitor is known to have high affinity with plasma proteins and is hardly excreted. To overcome such problems, preparation of a new compound of non-peptide type has been attempted (A. Katrin et al, Journal of Medicinal Chemistry, Vol. 41, 2194-2200, (1998)). Recently, a MMP inhibitor containing, as an active constituent, a flavon or anthocyanisine as disclosed in JP-A-8-104628, or a condensed thiophene derivative type MMP inhibitor as disclosed in JP-A-10-130271, is known. However, it has not been known that a medical composition containing, as an active constituent, a non-peptide type nitroetheneamine derivative or a salt thereof like the present invention, has a MMP inhibition activity, particularly a strong and selective enzyme inhibition activity against MMP-9 (gelatinase B/92 kDa type IV collagenase).
Some of the nitroetheneamine derivatives as active constituents of medical compositions of the present invention are known compounds as disclosed in e.g. WO90/5134, JP-A-2-171, JP-A-3-255072, JP-A-3-204848, East German Patent 107276, East German Patent 107674, JP-A-8-277253 and WO97/17954. These known compounds are usually employed mainly as insecticides, but the compounds disclosed in WO97/17954 are employed as painkillers. However, WO97/17954 discloses some of nitroetheneamine derivatives used in the present invention, merely by wording. It is not known at all that the above-mentioned known compounds have MMP inhibition activities. Further, JP-B-58-404956 discloses compounds similar to nitroetheneamine derivatives used as active constituents in the medical compositions of the present invention, as intermediates for compounds useful as active constituents of medical compositions, but such compounds are distinguished from the nitroetheneamine derivatives in that they do not have leaving groups having a xe2x80x9cNxe2x80x94Nxe2x80x9d structure. Further, in this publication, there is no such a disclosure that these compounds have MMP inhibition activities.
The present inventors have conducted an extensive study on the synthesis and the pharmacological activities of compounds having MMP inhibition activities, and as a result, have found nitroetheneamine derivatives or salts thereof which are useful as active constituents of the medical compositions of the present invention, particularly as non-peptide type compounds having strong and selective enzyme inhibition activities against MMP-9. Some of the nitroetheneamine derivatives or the salts thereof are novel compounds, and such novel compounds, the process for producing such novel compounds and the intermediates for the preparation of such novel compounds, are also included in the present invention.
Namely, the present invention relates to a medical composition containing, as an active constituent, a nitroetheneamine derivative represented by the formula (I): 
wherein
R1 is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted or a cyano group;
each of R2 and R3 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x94R7 group (wherein A is S, SO, SO2, SO3, CO or CO2, and R7 is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted or a heterocyclic group which may be substituted); or R2 and R3 may form, together with the N atom, a Nxe2x95x90CR8R9 group (wherein each of R8 and R9 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted, a cyano group, a nitro group, an alkoxy group which may be substituted, an alkylthio group which may be substituted, an aryloxy group which may be substituted or a xe2x80x94Axe2x80x94R7 group (wherein A and R7 are as defined above));
each of R4 and R5 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, a xe2x80x94Axe2x80x94R7 group (wherein A and R7 are as defined above), an amino group which may be substituted, a cyano group, an ester group, a hydroxyl group or an aryloxy group which may be substituted; or R4 and R5 may form, together with the N atom, a Nxe2x95x90CR8R9 group (wherein R8 and R9 are as defined above);
R6 is a hydrogen atom, a nitro group, a cyano group, a xe2x80x94Axe2x80x94R7 group (wherein A and R7 are as defined above), an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, a halogen atom or an amino group which may be substituted; and further
at least two selected from R1, R2, R3, R4 and R5 may together form a ring containing or not containing a hetero atom;
or a salt thereof.
The salt of the nitroetheneamine derivative represented by the above formula (I) may be any pharmaceutically acceptable salt. For example, a mineral acid salt such as a hydrochloride, a sulfate or a nitrate; an organic acid salt such as a p-toluenesulfonate, a propanesulfonate or a methanesulfonate; an alkali metal salt such as a potassium salt or a sodium salt; an alkaline earth metal salt such as a calcium salt; or an organic amine salt such as a triethanolamine salt or a tris (hydroxymethyl) aminomethane salt, may be mentioned. Further, among these salts, there may be ones having water of crystallization.
The alkyl moiety in the alkyl group which may be substituted, contained in R1, R2, R3, R4, R5, R6, R7, R8 and R9, in the alkoxy group which may be substituted, contained in R4, R5, R6, R8 and R9, or in the alkylthio group which may be substituted, contained in R8 and R9 in the above formula (I), may usually be one having a carbon number of from 1 to 18, such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an octyl group, a nonyl group, a decyl group or a nonadecyl group, and they include structural isomers of linear or branched aliphatic chains.
The alkenyl moiety of the alkenyl group which may be substituted, contained in R1, R2, R3, R4, R5, R6, R7, R8 and R9 in the above formula (I), may be one having a carbon number of from 2 to 18, such as a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a decenyl group or a nonadecenyl group, and they include structural isomers of linear or branched aliphatic chains.
The alkynyl moiety of the alkynyl group which may be substituted, contained in R1, R2, R3, R4, R5, R6, R7, R8 and R9 in the above formula (I), may be one having a carbon number of from 2 to 18, such as an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a decynyl group or a nonadecynyl group, and they include structural isomers of linear or branched aliphatic chains.
The cycloalkyl moiety of the cycloalkyl group which may be substituted, contained in R1, R2, R3, R4, R5, R6, R7, R8 and R9 in the above formula (I), may be one having a carbon number of from 3 to 8, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cyclooctyl group.
The cycloalkenyl moiety of the cycloalkenyl group which may be substituted, contained in R1, R2, R3, R4, R5, R6, R7, R8 and R9 in the above formula (I), may be one having a carbon number of from 5 to 8, such as a cyclopentenyl group, a cyclohexenyl group or a cyclooctenyl group.
The aryl moiety in the aryl group which may be substituted, contained in R1, R2, R3, R4, R5, R6, R7, R8 and R9, or in the aryloxy group which may be substituted, contained in R4, R5, R8 and R9, in the above formula (I), may, for example, be a phenyl group, a naphthyl group, a tetrahydronaphthyl group, an indanyl group, an adamanthyl group, a noradamanthyl group, a norbornanyl group or a norbornanonyl group.
The heterocyclic moiety in the heterocyclic group which may be substituted, contained in R1, R2, R3, R4, R5, R6, R7, R8 and R9 in the above formula (I), may, for example, be a mononuclear heterocyclic group such as a pyrrolyl group, pyrrolinyl group, a pyrrolidinyl group, a furanyl group, a dihydrofuranyl group, a tetrahydrofuranyl group, a thienyl group, a dihydrodithienyl group, a tetrahydrothienyl group, a pyrazolyl group, a pyrazolinyl group, a pyrazolidinyl group, an imidazolyl group, an imidazolinyl group, an imidazolidinyl group, an oxazolyl group, an oxazolinyl group, an oxazolidinyl group, an isoxazolyl group, an isoxazolinyl group, an isoxazolidinyl group, a thiazolyl group, a thiazolinyl group, a thiazolidinyl group, an isothiazolyl group, an isothiazolinyl group, an isothiazolidinyl group, an oxadiazolyl group, an oxadiazolinyl group, an oxadiazolidinyl group, a thiadiazolyl group, a thiadiazolinyl group, a thiadiazolidinyl group, a triazolyl group, a triazolinyl group, a triazolidinyl group, a tetrazolyl group, a tetrazolinyl group, a tetrazolidinyl group, a dioxolyl group, a dioxolanyl group, a dithiolyl group, a dithiolanyl group, a pyridyl group, a dihydropyridyl group, a tetrahydropyridyl group, a piperidinyl group, a pyrimidyl group, a dihydropyrimidyl group, a tetrahydropyrimidyl group, a hexahydropyrimidyl group, a pyridazinyl group, a dihydropyridazinyl group, a tetrahydropyridazinyl group, a hexahydropyridazinyl group, a pyrazinyl group, a dihydropyrazinyl group, a tetrahydropyrazinyl group, a piperazinyl group, a pyranyl group, a dihydropyranyl group, a tetrahydropyranyl group, a dioxynyl group, a dioxenyl group, a dioxanyl group, a dithianyl group or a morpholyl group; a condensed type polynuclear heterocyclic group such as a thienothienyl group, a dihydrocyclopentathienyl group, an indolyl group, a tetrahydroindolyl group, an isoindolyl group, a tetrahydroisoindolyl group, a benzothienyl group, a tetrahydrobenzothienyl group, a benzofuranyl group, a tetrahydrobenzofuranyl group, a benzoxazolyl group, a tetrahydrobenzoxazolyl group, a benzoisoxazolyl group, a tetrahydrobenzoisoxazolyl group, a benzothiazolyl group, a tetrahydrobenzothiazolyl group, a benzoisothiazolyl group, a tetrahydrobenzoisothiazolyl group, a benzoimidazolyl group, a tetrahydrobenzoimidazolyl group, a benzodioxolyl group, a benzodithiolyl group, a benzodioxanyl group, a benzodithianyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, a quinoxalinyl group, a phthalazinyl group, a naphthylidinyl group or a purinyl group; or a crosslinked type polynuclear heterocyclic ring such as a quinuclidinyl group.
The substituent(s) for the alkyl group which may be substituted, the alkenyl group which may be substituted and the alkynyl group which may be substituted, contained in R1, R2, R3, R4, R5, R6, R7, R8 and R9 in the above formula (I); for the amino group which may be substituted, contained in R2, R3, R4, R5 and R6; for the carbonyl group which may be substituted, contained in R8 and R9; for the alkoxy group which may be substituted, contained in R4, R5, R6, R8 and R9; and for the alkylthio group which may be substituted, contained in R8 and R9, may, for example, be a halogen atom, an alkoxy group, a haloalkoxy group, an alkylthio group, an alkenyloxy group, an alkynyloxy group, an alkenylthio group, an alkynylthio group, a cycloalkyl group, a cycloalkoxy group, a cycloalkenyl group, a cycloalkenyloxy group, a cycloalkylthio group, a cycloalkenylthio group, an alkoxycarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an aryloxycarbonyl group, a heteroaryloxycarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, an arylcarbonyloxy group, a heteroarylcarbonyloxy group, an aryl group, a heteroaryl group, an aryloxy group, an arylthio group, an amino group, an amino group which is substituted by an alkyl group, an amino group which is substituted by an alkenyl group, an amino group which is substituted by an alkynyl group, an amino group which is substituted by a cycloalkyl group, an amino group which is substituted by a cycloalkenyl group, an amino group which is substituted by an aryl group, an amino group which is substituted by a heteroaryl group, an amino group which is substituted by a n acyl group, an amino group which is substituted by an alkylsulfonyl group, an amino group which is substituted by an arylsulfonyl group, an amino group which is substituted by a heteroarylsulfonyl group, a cyano group, an acyl group, a nitro group, a carboxyl group, an aminocarbonyl group, a hydroxyaminocarbonyl group, a sulfonyl group, an alkylsulfonyl group, an arylsulfonyl group and a heteroarylsulfonyl group. The number of such substituent(s) or substituent(s) of such substituent(s) may be one or two or more, and such substituents may be the same or different.
The substituent(s) for the cycloalkyl group which may be substituted, the cycloalkenyl group which may be substituted, the aryl group which may be substituted and the heterocyclic group which may be substituted, contained in R1, R2, R3, R4, R5, R6, R7, R8 and R9 in the above formula (I), and for the aryloxy group which may be substituted, contained in R4, R5, R8 and R9, may, for example, be a halogen atom, an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a heteroaryl group, an alkoxy group, a haloalkoxy group, an alkoxyalkoxy group, an alkylthio group, an alkenyloxy group, an alkynyloxy group, an alkenylthio group, an alkynylthio group, a cycloalkyl group, a cycloalkoxy group, a cycloalkenyl group, a cycloalkenyloxy group, a cycloalkylthio group, a cycloalkenylthio group, an alkoxycarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an aryloxycarbonyl group, a heteroaryloxycarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, an arylcarbonyloxy group, a heteroarylcarbonyloxy group, an aryl group, an aryloxy group, a heteroaryloxy group, an arylthio group, a heteroarylthio group, an amino group, an amino group which is substituted by an alkyl group, an amino group which is substituted by an alkenyl group, an amino group which is substituted by an alkynyl group, an amino group which is substituted by a cycloalkyl group, an amino group which is substituted by a cycloalkenyl group, an amino group which is substituted by a n aryl group, an amino group which is substituted by a heteroaryl group, an amino group which is substituted by an acyl group, an amino group which is substituted by an alkylsulfonyl group, an amino group which is substituted by an arylsulfonyl group, an amino group which is substituted by a heteroarylsulfonyl group, a cyano group, an acyl group, a nitro group, a carboxyl group, an aminocarbonyl group, a hydroxyaminocarbonyl group, a sulfonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group and an arylalkyl group. The number of such substituent(s) or substituent(s) attached to such substituent(s) may be one or two or more, and such substituents may be the same or different.
Among the compounds represented by the above formula (I) or salts thereof, a nitroetheneamine derivative represented by the formula (I-1): 
wherein
R1xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted or a cyano group;
each of R2xe2x80x2 and R3xe2x80x2 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted (provided that a heterocyclic methyl group which may be substituted, is excluded), a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x2xe2x80x94R7xe2x80x2 group (wherein Axe2x80x2 is S, SO, SO2, SO3, CO or CO2, and R7xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted or a heterocyclic group which may be substituted); or R2xe2x80x2 and R3xe2x80x2 may form, together with the N atom, a Nxe2x95x90CR8xe2x80x2R9xe2x80x2 group (wherein each of R8xe2x80x2 and R9xe2x80x2 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted, a cyano group, a nitro group, an alkoxy group which may be substituted, an aryloxy group which may be substituted or a xe2x80x94Axe2x80x2xe2x80x94R7xe2x80x2 group (wherein Axe2x80x2 and R7xe2x80x2 are as defined above));
R4xe2x80x2 is an alkyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, an alkoxy group which may be substituted, a xe2x80x94Axe2x80x2xe2x80x94R7xe2x80x2 group (wherein Axe2x80x2 and R7xe2x80x2 are as defined above) or an amino group which may be substituted;
R5xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, an alkoxy group which may be substituted, a xe2x80x94Axe2x80x2xe2x80x94R7xe2x80x2 group (wherein Axe2x80x2 and R7xe2x80x2 are as defined above) or an amino group which may be substituted; or R4xe2x80x2 and R5xe2x80x2 may form, together with the N atom, a Nxe2x95x90CR8xe2x80x2R9xe2x80x2 group (wherein R8xe2x80x2 and R9xe2x80x2 are as defined above);
R6xe2x80x2 is a hydrogen atom, a nitro group, a cyano group, a xe2x80x94Axe2x80x2xe2x80x94R7xe2x80x2 group (wherein Axe2x80x2 and R7xe2x80x2 are as defined above), an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, a halogen atom or an amino group which may be substituted; and further
at least two selected from R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2 and R5xe2x80x2 may together form a ring containing or not containing a hetero atom;
provided that (1) a case where R1xe2x80x2 or R4xe2x80x2 is an alkyl group substituted by a hetero-ring which may be substituted, (2) a case where R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R5xe2x80x2 and R6xe2x80x2 are all hydrogen atoms and R4xe2x80x2 is 
xe2x80x83(wherein R10xe2x80x2 is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or a dialkylamino group) and (3) a case where R1xe2x80x2, R3xe2x80x2, R5xe2x80x2 and R6xe2x80x2 are all hydrogen atoms, and R2xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted or an aryl group which may be substituted, and R4xe2x80x2 is 
xe2x80x83(wherein j is an integer of from 1 to 6), are excluded; or a salt thereof, is a compound which heretofore has not specifically been known.
Among the nitroetheneamine derivatives represented by the above formula (I-1) or salts thereof, as compounds which heretofore have not specifically been known, a nitroetheneamine derivative wherein R1xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted or a cyano group;
each of R2xe2x80x2 and R3xe2x80x2 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted (provided that a heterocyclic methyl group which may be substituted, is excluded), a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x2xe2x80x94R7xe2x80x2 group (wherein Axe2x80x2 is S, SO, SO2, SO3, CO or CO2, and R7xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted or a heterocyclic group which may be substituted); or R2xe2x80x2 and R3xe2x80x2 may form, together with the N atom, a Nxe2x95x90CR8xe2x80x3R9xe2x80x3 group (wherein each of R8xe2x80x3 and R9xe2x80x3 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted or an alkoxy group which may be substituted);
R4xe2x80x2 is an alkyl group which may be substituted, an alkoxyphenyl group, a haloalkyloxyphenyl group, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an alkoxy group which may be substituted, a xe2x80x94Axe2x80x2xe2x80x94R7xe2x80x2 group (wherein Axe2x80x2 and R7xe2x80x2 are as defined above) or an amino group which may be substituted;
R5xe2x80x2 is a hydrogen atom, an alkyl group, an alkoxyphenyl group, a haloalkyloxyphenyl group, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an alkoxy group which may be substituted, a xe2x80x94Axe2x80x2xe2x80x94R7xe2x80x2 group (wherein Axe2x80x2 and R7xe2x80x2 are as defined above) or an amino group which may be substituted;
R6xe2x80x2 is a hydrogen atom, a nitro group, a cyano group or a xe2x80x94Axe2x80x2xe2x80x94R7xe2x80x2 group (wherein Axe2x80x2 and R7xe2x80x2 are as defined above) or an alkyl group which may be substituted;
or R4xe2x80x2 and R5xe2x80x2 may form, together with the N atom, a Nxe2x95x90CR8xe2x80x3R9xe2x80x3 group (wherein R8xe2x80x3 and R9xe2x80x3 are as defined above); and further
at least two selected from R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2 and R5xe2x80x2 may together form a ring containing or not containing a hetero atom;
provided that (1) a case where R1xe2x80x2 or R4xe2x80x2 is an alkyl group substituted by a hetero-ring which may be substituted, (2) a case where R1xe2x80x2, R3xe2x80x2, R5xe2x80x2 and R6xe2x80x2 are all hydrogen atoms, R2xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted or an aryl group which may be substituted, and R4xe2x80x2 is 
xe2x80x83(wherein j is an integer of from 1 to 6), and (3) a case wherein R1xe2x80x2 is a hydrogen atom; each of R2xe2x80x2 and R3xe2x80x2 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted or a phenyl group which may be substituted; R4xe2x80x2 is an alkyl which may be substituted, a phenyl group which may be substituted, a xe2x80x94Axe2x80x2xe2x80x94R7xe2x80x2 group (wherein Axe2x80x2 and R7xe2x80x2 are as defined above) or an amino group which may be substituted; R5xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted or a phenyl group which may be substituted; and R6xe2x80x2 is a hydrogen atom, are excluded;
or a salt thereof, is a preferred compound.
Among the above-mentioned preferred compounds of the formula (I-1), a nitroetheneamine derivative wherein R1xe2x80x2 is a hydrogen atom; R2xe2x80x2 is a hydrogen atom, a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x3xe2x80x94R7xe2x80x3 group (wherein Axe2x80x3 is CO, CO2 or SO2, and R7xe2x80x3 is an alkyl group which may be substituted or an aryl group which may be substituted); R3xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted (provided that a heterocyclic methyl group which may be substituted, is excluded), a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x3xe2x80x94R7xe2x80x3 group (wherein Axe2x80x3 and R7xe2x80x3 are as defined above); or R2xe2x80x2 and R3xe2x80x2 may together form, a Nxe2x95x90CR8xe2x80x3R9xe2x80x3 group (wherein each of R8xe2x80x3 and R9xe2x80x3 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted or an alkoxy group which may be substituted); R4xe2x80x2 is an alkyl group which may be substituted (provided that a heterocyclic alkyl group which may be substituted, is excluded), an alkoxyphenyl group, a haloalkyloxyphenyl group, a cycloalkyl group which may be substituted, an alkylsulfonyl group which may be substituted, an alkenylsulfonyl group which may be substituted, an alkynylsulfonyl group which may be substituted, a cycloalkylsufonyl group which may be substituted, a cycloalkenylsulfonyl group which may be substituted, an arylsulfonyl group which may be substituted, a sulfonyl group substituted by a hetero ring which may be substituted or an amino group which may be substituted; R5xe2x80x2 is a hydrogen atom; R6xe2x80x2 is a hydrogen atom or an alkyl group; and further R2xe2x80x2 and R3xe2x80x2 may together form a ring containing or not containing a hetero atom; provided that (1) a case where R1xe2x80x2, R2xe2x80x2, R5xe2x80x2 and R6xe2x80x2 are hydrogen atoms; R3xe2x80x2 is a hydrogen atom or an alkyl group which may be substituted; R4xe2x80x2 is an alkyl which may be substituted, an alkoxyphenyl group which may be substituted, a haloalkyloxyphenyl group which may be substituted, an alkylsulfonyl group which may be substituted, an alkenylsulfonyl group which may be substituted, an alkynylsulfonyl group which may be substituted, a cycloalkylsufonyl group which may be substituted, a cycloalkenylsulfonyl group which may be substituted, an arylsulfonyl group which may be substituted or a sulfonyl group substituted by a hetero ring which may be substituted, and (2) a case where R1xe2x80x2, R3xe2x80x2, R5xe2x80x2 and R6xe2x80x2 are hydrogen atoms, R2xe2x80x2 is a heterocyclic group (provided that a heterocyclic group substituted by at least one halogen atom, is excluded), and R4xe2x80x2 is an alkyl group which may be substituted, are excluded; or a salt thereof, is a novel compound.
The above novel compound is a compound particularly excellent as an active constituent for a matrix metalloproteinase inhibitor and can be used as an active constituent for a medical composition such as {circle around (1)} an inhibitor against at least one matrix metalloproteinase selected from MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9, particularly a MMP-9 inhibitor; {circle around (2)} an angiogenesis inhibitor; {circle around (3)} an anticancer drug; {circle around (4)} a tumor cell infiltration inhibitor; {circle around (5)} a tumor metastatis inhibitor; or {circle around (6)} a therapeutic or preventive agent for rheumatoid arthritis. Among these novel compounds, the following compounds are particularly excellent as active constituents for matrix metalloproteinase inhibitors.
(1) A nitroetheneamine derivative of the above formula (I-1), wherein R1xe2x80x2 is a hydrogen atom; R2xe2x80x2 is a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x3xe2x80x94R7xe2x80x3 group (wherein Axe2x80x3 is CO, CO2 or SO2, and R7xe2x80x3 is an alkyl group which may be substituted or an aryl group which may be substituted); R3xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted (provided that a heterocyclic methyl group which may be substituted, is excluded), a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x3xe2x80x94R7xe2x80x3 group (wherein Axe2x80x3 and R7xe2x80x3 are as defined above); or R2xe2x80x2 and R3xe2x80x2 may together form a Nxe2x95x90CR8xe2x80x3R9xe2x80x3 group (wherein each of R8xe2x80x3 and R9xe2x80x3 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted or an alkoxy group which may be substituted) or form a ring containing or not containing a hetero atom; R4xe2x80x2 is an alkylsulfonyl group which may be substituted, an alkenylsulfonyl group which may be substituted, an alkynylsulfonyl group which may be substituted, a cycloalkylsufonyl group which may be substituted, a cycloalkenylsulfonyl group which may be substituted, an arylsulfonyl group which may be substituted, a sulfonyl group substituted by a hetero ring which may be substituted or an amino group which may be substituted; R5xe2x80x2 is a hydrogen atom; and R6xe2x80x2 is a hydrogen atom or an alkyl group; or a salt thereof.
(2) A nitroetheneamine derivative of the above formula (I-1), wherein R1xe2x80x2 is a hydrogen atom; R2xe2x80x2 is a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x3xe2x80x94R7xe2x80x3 group (wherein Axe2x80x3 is CO, CO2 or SO2, and R7xe2x80x3 is an alkyl group which may be substituted or an aryl group which may be substituted); R3xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted (provided that a heterocyclic methyl group which may be substituted, is excluded), a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x3xe2x80x94R7xe2x80x3 group (wherein Axe2x80x3 and R7xe2x80x3 are as defined above); or R2xe2x80x2 and R3xe2x80x2 may together form a Nxe2x95x90CR8xe2x80x3R9xe2x80x3 group (wherein each of R8xe2x80x3 and R9xe2x80x3 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted or an alkoxy group which may be substituted); R4xe2x80x2 is an alkylsulfonyl group which may be substituted, an alkenylsulfonyl group which may be substituted, an alkynylsulfonyl group which may be substituted, a cycloalkylsufonyl group which may be substituted, a cycloalkenylsulfonyl group which may be substituted, an arylsulfonyl group which may be substituted, a sulfonyl group substituted by a hetero ring which may be substituted or an amino group which may be substituted; R5xe2x80x2 is a hydrogen atom; and R6xe2x80x2 is a hydrogen atom or an alkyl group; or a salt thereof.
(3) A nitroetheneamine derivative of the above formula (I-1), wherein R1xe2x80x2 is a hydrogen atom; R2xe2x80x2 is a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x3xe2x80x94R7xe2x80x3 group (wherein Axe2x80x3 is CO, CO2 or SO2, and R7xe2x80x3 is an alkyl group which may be substituted or an aryl group which may be substituted); R3xe2x80x2 is a hydrogen atom, an alkyl group which may be substituted (provided that a heterocyclic methyl group which may be substituted, is excluded), a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x3xe2x80x94R7xe2x80x3 group (wherein Axe2x80x3 and R7xe2x80x3 are as defined above); or R2xe2x80x2 and R3xe2x80x2 may together form a Nxe2x95x90CR8xe2x80x3R9xe2x80x3 group (wherein each of R8xe2x80x3 and R9xe2x80x3 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted or an alkoxy group which may be substituted); R4xe2x80x2 is an alkylsulfonyl group which may be substituted, an arylsulfonyl group which may be substituted, or an amino group which may be substituted; R5xe2x80x2 is a hydrogen atom; and R6xe2x80x2 is a hydrogen atom or an alkyl group; or a salt thereof.
(4) A nitroetheneamine derivative of the above formula (I-1), wherein R1xe2x80x2 is a hydrogen atom; R2xe2x80x2 is a heterocyclic group which may be substituted or a xe2x80x94Axe2x80x3xe2x80x94R7xe2x80x3 group (wherein Axe2x80x3 is CO, CO2 or SO2, and R7xe2x80x3 is an alkyl group which may be substituted or an aryl group which may be substituted); R3xe2x80x2 is a hydrogen atom or methyl; or R2xe2x80x2 and R3xe2x80x2 may together form a Nxe2x95x90CR8xe2x80x3R9xe2x80x3 group (wherein each of R8xe2x80x3 and R9xe2x80x3 which are independent of each other, is a hydrogen atom, an alkyl group which may be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted or an alkoxy group which may be substituted); R4xe2x80x2 is an alkylsulfonyl group which may be substituted, an arylsulfonyl group which may be substituted, or an amino group which may be substituted; R5xe2x80x2 is a hydrogen atom; and R6xe2x80x2 is a hydrogen atom or an alkyl group; or a salt thereof.
(5) A nitroetheneamine derivative of the formula (I-1), wherein R1xe2x80x2 is a hydrogen atom; R2xe2x80x2 and R3xe2x80x2 may together form a ring containing or not containing a hetero atom; R4xe2x80x2 is an alkyl group which may be substituted, an alkoxyphenyl group, a haloalkyloxyphenyl group, a cycloalkyl group which may be substituted, an alkylsulfonyl group which may be substituted, an alkenylsulfonyl group which may be substituted, an alkynylsulfonyl group which may be substituted, a cycloalkylsufonyl group which may be substituted, a cycloalkenylsulfonyl group which may be substituted, an arylsulfonyl group which may be substituted or a sulfonyl group substituted by a hetero ring which may be substituted; R5xe2x80x2 is a hydrogen atom; and R6xe2x80x2 is a hydrogen atom or an alkyl group; or a salt thereof.
(6) A nitroetheneamine derivative of the formula (I-1), wherein R1xe2x80x2 is a hydrogen atom; R2xe2x80x2 and R3xe2x80x2 may together form a ring containing or not containing a hetero atom; R4xe2x80x2 is an alkylsulfonyl group which may be substituted or an arylsulfonyl group which may be substituted; R5xe2x80x2 is a hydrogen atom; and R6xe2x80x2 is a hydrogen atom or an alkyl group; or a salt thereof.
The compound of the above formula (I) or a salt thereof can be produced by a known process for producing similar compounds (such as the process disclosed in JP-A-2-171) or a process similar thereto. However, as preferred embodiments, the following processes 1 to 12 may be exemplified.
A process for producing a nitroetheneamine derivative of the above formula (I), which comprises:
(1) a first step of reacting a compound represented by the formula (II): 
xe2x80x83wherein Z is an alkyl group or an arylalkyl group, and R6 is as defined above, with a compound represented by the formula (III): 
xe2x80x83wherein Y is hydrogen or an alkali metal element, and R4 and R5 are as defined above, to obtain a compound represented by the formula (IV): 
xe2x80x83wherein Z, R4, R5 and R6 are as defined above, and
(2) a second step of reacting the compound of the above formula (IV) obtained in the first step, with a compound represented by the formula (V): 
xe2x80x83wherein Y is hydrogen or an alkali metal element, and R1, R2 and R3 are as defined above, to obtain a nitroetheneamine derivative of the above formula (I).
A process for producing a nitroetheneamine derivative of the above formula (I), which comprises:
(1) a first step of reacting a compound of the above formula (II) with a compound of the above formula (V) to obtain a compound of the formula (VI): 
xe2x80x83wherein Z, R1, R21, R3 and R6 are as defined above, and
(2) a second step of reacting the above compound of the above formula (VI) obtained in the first step, with a compound of the formula (III) to obtain a nitroetheneamine derivative of the above formula (I).
Here, the compound of the above formula (II) and the compound of the above formula (III) as the starting materials for Process 1 and Process 2 can be produced by known processes or processes similar thereto.
The respective reactions in Process 1 and Process 2 can be carried out in the presence of a suitable solvent. The solvent to be specifically used, may, for example, be an alcohol such as methanol, ethanol, propanol or butanol; an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroin or petroleum benzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such as acetonitrile or propionitrile; an acid amide such as dimethylformamide or dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amide such as hexamethylphosphoramide; a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and a solvent mixture thereof.
In order to carry out the respective reactions in Process 1 and Process 2 efficiently, it is preferred to carry out the reactions in the presence of a base. The base to be specifically used, may, for example, be an organic base such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkali metal such as lithium, sodium or potassium; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; or an alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide. Further, the compound of the above formula (III) and/or the compound of the above formula (V) will also act as a base.
The respective reactions in Process 1 and Process 2 are carried out usually at a reaction temperature of from xe2x88x9230 to 1500xc2x0 C., preferably at a reaction temperature of from 0 to 1000xc2x0 C. The reaction time is usually from 0.1 to 48 hours.
In the first step of Process 1, the compound of the above formula (III) can be used in an amount of from 1 to 1.2 equivalents per mol of the compound of the above formula (II). If the compound of the above formula (III) is used excessively, in addition to the compound of the above formula (IV), a compound represented by the formula (VII): 
wherein R4, R5 and R6 are as defined above, will be formed as a by-product, such being undesirable. Further, in the second step of Process 1, the compound of the above formula (V) can be used in an amount of from 1 to 1.5 equivalents per mol of the compound of the above formula (IV), but it may be used excessively without any particular problem.
In the first step of Process 2, the compound of the above formula (V) can be used in an amount of from 1 to 1.2 equivalents per mol of the compound of the above formula (II). If the compound of the above formula (V) is used excessively, in addition to the compound of the above formula (VI), a compound represented by the formula (VIII): 
wherein R1, R2, R3 and R6 are as defined above, will be produced as a by-product, such being undesirable. Further, in the second step of Process 2, the compound of the above formula (III) can be used in an amount of from 1 to 1.5 equivalents per mol of the compound of the above formula (VI), but it may be used excessively without any particular problem.
The compound of the above formula (IV) obtained in Process 1 and the compound of the above formula (VI) obtained in Process 2, may be supplied to the subsequent reaction for producing a compound of the above formula (I) directly in the form of the reaction mixture or after separation and purification by a known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization or chromatography.
Various reaction conditions in Process 1 i.e. (1) the type and/or the amount of the compound of the above formula (II), (2) the type and/or the amount of the compound of the above formula (III), (3) with or without use of a solvent in the reaction of the first step, (4) the type and/or the amount of the solvent in the reaction of the first step, (5) with or without use of a base in the reaction of the first step, (6) the type and/or the amount of the base in the reaction of the first step, (7) the reaction temperature in the first step, (8) the reaction time in the first step, (9) the type of the compound of the above formula (IV) as an intermediate product in the first step, (10) with or without separation and purification of the compound of the above formula (IV), (11) the type and/or the amount of the compound of the formula (V), (12) with or without use of a solvent in the reaction of the second step, (13) the type and/or the amount of the solvent in the reaction of the second step, (14) with or without use of a base in the reaction of the second step, (15) the type and/or the amount of the base in the reaction of the second step, (16) the reaction temperature in the reaction of the second step, (17) the reaction time in the reaction of the second step, and (18) the type of the compound of the formula (I) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above-mentioned various reaction conditions are also in the scope of Process 1.
Various reaction conditions in Process 2 i.e. (1) the type and/or the amount of the compound of the above formula (II), (2) the type and/or the amount of the compound of the above formula (V), (3) with or without use of a solvent in the reaction of the first step, (4) the type and/or the amount of the solvent in the reaction of the first step, (5) with or without use of a base in the reaction of the first step, (6) the type and/or the amount of the base in the reaction of the first step, (7) the reaction temperature in the first step, (8) the reaction time in the first step, (9) the type of the compound of the above formula (VI) as an intermediate product in the first step, (10) with or without separation and purification of the compound of the above formula (VI), (11) the type and/or the amount of the compound of the formula (III), (12) with or without use of a solvent in the reaction of the second step, (13) the type and/or the amount of the solvent in the reaction of the second step, (14) with or without use of a base in the reaction of the second step, (15) the type and/or the amount of a base in the reaction of the second step, (16) the reaction temperature in the reaction of the second step, (17) the reaction time in the reaction of the second step, and (18) the type of the compound of the formula (I) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above various reaction conditions are also in the scope of Process 2.
A process for producing a nitroetheneamine derivative of the above formula (I), which comprises:
(1) a first step of reacting a compound represented by the formula (IX): 
xe2x80x83wherein X is a halogen atom, and R6 is as defined above, and/or a compound represented by the formula (X): O2Nxe2x80x94CH(R6)CX3, wherein X and R6 are as defined above, with a compound of the above formula (III) to obtain a compound represented by the formula (XI): 
xe2x80x83wherein X, R4, R5 and R6 are as defined above, and
(2) a second step of reacting a compound of the above formula (XI) obtained in the first step, with a compound of the above formula (V) to obtain a nitroetheneamine derivative of the above formula (I).
A process for producing a nitroetheneamine derivative of the above formula (I) which comprises:
(1) a first step of reacting a compound of the above formula (IX) and/or a compound of the above formula (X), with a compound of the above formula (V) to obtain a compound represented by the formula (XII): 
xe2x80x83wherein X, R1, R2, R3 and R6 are as defined above, and
(2) a second step of reacting the compound of the above formula (XII) obtained in the first step with a compound of the above formula (III) to obtain a nitroetheneamine derivative of the above formula (I).
Further, the compound of the above formula (IX) and the compound of the above formula (X) which are the starting materials in Process 3 and Process 4, can be produced by a known method disclosed, for example, in Journal of Organic Chemistry, Vol. 25, 1312 (1960) or a method similar thereto.
The respective reactions of Process 3 and Process 4 can be carried out in the presence of a suitable solvent. The solvent to be specifically used, may, for example, be an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroin or petroleum benzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such as acetonitrile or propionitrile; an acid amide such as dimethylformamide or dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amide such as hexamethylphosphoramide; a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and a solvent mixture thereof.
In Process 3 and Process 4, in order to carry out the respective reactions efficiently, it is preferred to carry out the reaction in the presence of a base. The base to be specifically used, may, for example, be an organic base such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0]-7-undecene or N,N-dimethylaniline; an alkali metal such as lithium, sodium or potassium; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; or an alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide. Further, the compound of the above formula (III) and/or the compound of the above formula (V) also acts as a base.
The respective reactions of Process 3 and Process 4 are carried out usually at a reaction temperature of from xe2x88x9230 to 150xc2x0 C., preferably at a reaction temperature of from 0 to 80xc2x0 C. The reaction time is usually from 0.1 to 48 hours.
In the first step of Process 3, the compound of the above formula (III) can be used in an amount of from 0.8 to 2 equivalents, preferably from 1 to 1.2 equivalents, per mol of the compound of the above formula (IX). Further, in the second step of Process 3, the compound of the above formula (III) can be used in an amount of from 1 to 1.5 equivalents per mol of the compound of the above formula (XI). However, it may be used excessively without any particular problem.
In the first step of Process 4, the compound of the above formula (V) can be used in an amount of from 1 to 2 equivalents, preferably from 1 to 1.2 equivalents, per mol of the compound of the above formula (IX). Further, in the second step of Process 4, the compound of the above formula (III) can be used in an amount of from 1 to 1.5 equivalents per mol of the compound of the above formula (XII). However, it may be used excessively without any particular problem.
The compound of the above formula (XI) obtained in Process 3, and the compound of the above formula (XII) obtained in Process 4, may be supplied to the subsequent reaction for producing the compound of the above formula (I) directly in the form of the reaction mixture or after separation and purification by a known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization or chromatography.
Various reaction conditions in Process 3 i.e. (1) the type of the compound of the above formula (IX) and/or the compound of the above formula (X), (2) the amount of the compound of the above formula (IX) and the compound of the above formula (X), (3) the type and/or the amount of the compound of the above formula (III), (4) with or without use of a solvent in the reaction of the first step, (5) the type and/or the amount of the solvent in the reaction in the first step, (6) with or without use of a base in the reaction of the first step, (7) the type and/or the amount of a base in the reaction of the first step, (8) the reaction temperature in the first step, (9) the reaction time in the first step, (10) the type of the compound of the above formula (XI) which is an intermediate product in the first step, (11) with or without separation and purification of the compound of the above formula (XI), (12) the type and/or the amount of the compound of the formula (V), (13) with or without use of a solvent in the reaction of the second step, (14) the type and/or the amount of the solvent in the reaction of the second step, (15) with or without use of a base in the reaction of the second step, (16) the type and/or the amount of the base in the reaction of the second step, (17) the reaction temperature in the reaction of the second step, (18) the reaction time in the reaction of the second step, and (19) the type of the compound of the formula (I) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above various reaction conditions are also within the scope of Process 3.
Various reaction conditions in Process 4 i.e. (1) the type of the compound of the above formula (IX) and/or the compound of the above formula (X), (2) the amount of the compound of the above formula (IX) and the compound of the above formula (X), (3) the type and/or the amount of the compound of the above formula (V), (4) with or without use of a solvent in the reaction of the first step, (5) the type and/or the amount of the solvent in the reaction of the first step, (6) with or without use of a base in the reaction of the first step, (7) the type and/or the amount of a base in the reaction of the first step, (8) the reaction temperature in the first step, (9) the reaction time in the first step, (10) the type of the compound of the above formula (XII) which is an intermediate product in the first step, (11) with or without separation and purification of the compound of the above formula (XII), (12) the type and/or the amount of the compound of the formula (III), (13) with or without use of a solvent in the reaction of the second step, (14) the type and/or the amount of the solvent in the reaction of the second step, (15) with or without use of a base in the reaction of the second step, (16) the type and/or the amount of the base in the reaction of the second step, (17) the reaction temperature in the reaction of the second step, (18) the reaction time in the reaction of the second step, and (19) the type of the compound of the formula (I) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combination of the above various reaction conditions are also within the scope of Process 4.
A process for producing a nitroetheneamine derivative of the after-mentioned formula (Ixe2x80x2), which comprises:
(1) a first step of reacting a compound represented by the above formula (V) with a compound represented by the formula (XIII): R4-NCS, wherein R4 is as defined above, to obtain a compound represented by the formula (XIV): 
xe2x80x83wherein R1, R2, R3 and R4 are as defined above, and
(2) a second step of reacting the compound of the above formula (XIV) obtained in the first step with a compound of the formula (XV): Z-X wherein Z and X are as defined above, to obtain a compound of the formula (XVI): 
xe2x80x83wherein Z, R1, R2, R3 and R4 are as defined above, and
(3) a third step of reacting the compound of the above formula (XVI) obtained in the second step with a compound represented by the formula (XVII): R6xe2x80x94CH2NO2, wherein R6 is as defined above, to obtain a nitroetheneamine derivative of the formula (Ixe2x80x2): 
xe2x80x83wherein R1, R2, R3, R4 and R6 are as defined above.
Here, the compound of the above formula (Ixe2x80x2) is a compound of the above formula (I), and a compound where R5 is a hydrogen atom.
The reaction in the first step of Process 5 can be carried out in the presence of a suitable solvent. The solvent to be specifically used, may, for example, be an alcohol such as methanol, ethanol, propanol or butanol; an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroin or petroleum benzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such as acetonitrile or propionitrile; an acid amide such as dimethylformamide or dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amide such as hexamethylphosphoramide; a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and a solvent mixture thereof.
In the first step of Process 5, in order to carry out the reaction efficiently, it is preferred to carry out the reaction in the presence of a base. The base to be specifically used, may, for example, be an organic base such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0]-7-undecene or N,N-dimethylaniline; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; or an alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate. Further, the compound of the above formula (V) also acts as a base.
The reaction in the first step of Process 5 is carried out usually at a reaction temperature of from xe2x88x9230 to 200xc2x0 C., preferably at a reaction temperature of from 0 to 150xc2x0 C. The reaction time is usually from 0.1 to 48 hours.
In the first step of Process 5, the compound of the above formula (XIII) is used in an amount of from 0.8 to 2 equivalents, preferably from 1 to 1.2 equivalents, per mol of the compound of the above formula (V). The obtained compound of the above formula (XIV) may be supplied to the reaction of the second step directly in the form of the reaction mixture or after separation and purification by a known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization or chromatography.
The reaction in the second step of Process 5 can be carried out in the presence of a suitable solvent. The solvent to be specifically used, may, for example, be an alcohol such as methanol, ethanol, propanol or butanol; a ketone such as acetone, methyl ethyl ketone, dimethyl ketone or diethyl ketone; an ester such as methyl acetate, ethyl acetate, butyl acetate, methyl formate, ethyl formate, butyl formate or ethyl propionate; an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroin or petroleum benzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such as acetonitrile or propionitrile; an acid amide such as dimethylformamide or dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amide such as hexamethylphosphoramide; a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and a solvent mixture thereof.
In the second step of Process 5, in order to carry out the reaction efficiently, it is preferred to carry out the reaction in the presence of a base. The base to be specifically used may, for example, be an organic base such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0]-7-undecene or N,N-dimethylaniline; an alkali metal such as lithium, sodium or potassium; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; or an alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide.
The reaction in the second step of Process 5 is carried out usually at a temperature of from xe2x88x9230 to 150xc2x0 C., preferably at a temperature of from 0 to 100xc2x0 C. The reaction time is usually from 0.1 to 48 hours.
In the reaction of the second step in Process 5, the compound of the above formula (XV) can be used in an amount of at least 1 equivalent per mol of the compound of the above formula (XIV). As the compound of the above formula (XV), various compounds may be employed. For example, benzyl bromide or methyl iodide may be employed. The obtained compound of the above formula (XVI) may be supplied to the reaction of the third step directly in the form of the reaction mixture or after separation and purification by a known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization or chromatography.
The reaction of the third step in Process 5 can be carried out in the presence of a suitable solvent. The solvent to be specifically used may, for example, be an alcohol such as methanol, ethanol, propanol or butanol; an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroin or petroleum benzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such as acetonitrile or propionitrile; an acid amide such as dimethylformamide or dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amide such as hexamethylphosphoramide; a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and a solvent mixture thereof.
In the third step of Process 5, in order to carry out the reaction efficiently, it is preferred to carry out the reaction in the presence of a base. The base to be specifically used may, for example, be an organic base such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0]-7-undecene or N,N-dimethylaniline; an alkali metal such as lithium, sodium or potassium; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; or an alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide.
The reaction in the third step of Process 5 can be carried out usually at a reaction temperature of from xe2x88x9230 to 200xc2x0 C., preferably at a reaction temperature of from 0 to 150xc2x0 C. The reaction time is usually from 0.1 to 48 hours.
In the reaction of the third step in Process 5, the compound of the above formula (XVII) can be used in an amount of from 1 to 5 equivalents per mol of the compound of the above formula (XVI).
Various reaction conditions in Process 5 i.e. (1) the type and/or the amount of the compound of the formula (V), (2) the type and/or the amount of the compound of the formula (XIII), (3) with or without use of a solvent in the reaction of the first step, (4) the type and/or the amount of the solvent in the reaction of the first step, (5) with or without use of a base in the reaction of the first step, (6) the type and/or the amount of the base in the reaction of the first step, (7) the reaction temperature of the first step, (8) the reaction time of the first step, (9) the type of the compound of the above formula (XIV) which is an intermediate product in the first step, (10) with or without separation and purification of the compound of the formula (XIV) which is an intermediate product in the first step, (11) the type and/or the amount of the compound of the formula (XV), (12) with or without use of a solvent in the reaction of the second step, (13) the type and/or the amount of the solvent in the reaction of the second step, (14) with or without use of a base in the reaction of the second step, (15) the type and/or the amount of the base in the reaction of the second step, (16) the reaction temperature of the second step, (17) the reaction time of the second step, (18) the type of the compound of the above formula (XVI) which is an intermediate product in the second step, (19) with or without separation and purification of the compound of the formula (XVI) which is an intermediate product in the second step, (20) the type and/or the amount of the compound of the formula (XVII), (21) with or without use of a solvent in the reaction of the third step, (22) the type and/or the amount of the solvent in the reaction of the third step, (23) with or without use of a base in the reaction of the second step, (24) the type and/or the amount of a base in the reaction of the second step, (25) the reaction temperature of the third step, (26) the reaction time of the third step, and (27) the type of the compound of the formula (Ixe2x80x2) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above various reaction conditions are also within the scope of Process 5.
A process for producing a nitroetheneamine derivative of the above formula (I), which comprises:
(1) a first step of reacting a compound represented by the formula (XVIII): 
xe2x80x83wherein R4, R5 and R6 are as defined above, with a halogenating agent to obtain a compound of the above formula (XI), and
(2) a second step of reacting the compound of the above formula (XI) obtained in the first step with a compound of the above formula (V) to obtain a compound of the above formula (I).
A process for producing a nitroetheneamine derivative of the above formula (I), which comprises:
(1) a first step of reacting a compound represented by the formula (XIX): 
xe2x80x83wherein R1, R2, R3 and R6 are as defined above, with a halogenating agent to obtain a compound of the above formula (XII), and
(2) a second step of reacting the compound of the above formula (XII) obtained in the first step with a compound of the above formula (III) to obtain a compound of the above formula (I).
Here, the compound of the above formula (XVIII) and the compound of the above formula (XIX) which are the starting materials in Process 6 and Process 7, can be produced by a known method or a method similar thereto.
The reactions of the first step of Process 6 and the first step of Process 7, are preferably carried out in the presence of a solvent. The solvent to be specifically used may, for example, be an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroin or petroleum benzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and a solvent mixture thereof. The reaction is preferably carried out in a system where no water is present.
The halogenating agent to be used in the reactions of the first step of Process 6 and the first step of Process 7, may, for example, be phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride, thionyl chloride or oxalyl chloride. The amount is from 1 to 10 equivalents, preferably from 1 to 5 equivalents, per mol of the compound of the above formula (XVIII) or the compound of the above formula (XIX). Further, it is preferred to let a base be present to capture hydrogen chloride formed by this reaction. Such a base may, for example, be an organic base such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline.
The reactions of the first step of Process 6 and the first step of Process 7 are carried out usually at a reaction temperature of from xe2x88x9230 to 200xc2x0 C., preferably at a reaction temperature of from 0 to 150xc2x0 C. The reaction time is usually from 0.1 to 48 hours.
The compound of the above formula (XI) obtained in the first step of Process 6 and the compound of the above formula (XII) obtained in the first step of Process 7, may be supplied to the reaction of the second step of Process 6 which is the same reaction as in the second step of Process 3 and to the reaction of the second step of Process 7 which is the same reaction as in the second step of Process 4, directly in the form of the reaction mixtures or after separation and purification by a known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization or chromatography.
Various reaction conditions in Process 6 i.e. (1) the type and/or the amount of the compound of the formula (XVIII), (2) the type and/or the amount of the halogenating agent, (3) with or without use of a solvent in the reaction of the first step, (4) the type and/or the amount of the solvent in the reaction of the first step, (5) with or without use of a base in the reaction of the first step, (6) the type and/or the amount of the base in the reaction of the first step, (7) the reaction temperature of the first step, (8) the reaction time of the first step, (9) the type of the compound of the formula (XI) which is an intermediate product in the first step, (10) with or without separation and purification of the compound of the above formula (XI), (11) the type and/or the amount of the compound of the formula (V), (12) with or without use of a solvent in the reaction of the second step, (13) the type and/or the amount of the solvent in the reaction of the second step, (14) with or without use of a base in the reaction of the second step, (15) the type and/or the amount of the base in the reaction of the second step, (16) the reaction temperature in the reaction of the second step, (17) the reaction time in the reaction of the second step, and (18) the type of the compound of the formula (I) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above various reaction conditions are also within the scope of Process 6.
Various reaction conditions in Process 7 i.e. (1) the type and/or the amount of the compound of the formula (XIX), (2) the type and/or the amount of the halogenating agent, (3) with or without use of a solvent in the reaction of the first step, (4) the type and/or the amount of the solvent in the reaction of the first step, (5) with or without use of a base in the reaction of the first step, (6) the type and/or the amount of a base in the reaction of the first step, (7) the reaction temperature of the first step, (8) the reaction time of the first step, (9) the type of the compound of the formula (XII) which is an intermediate product in the first step, (10) with or without separation and purification of the compound of the above formula (XII), (11) the type and/or the amount of the compound of the formula (III), (12) with or without use of a solvent in the reaction of the second step, (13) the type and/or the amount of the solvent in the reaction of the second step, (14) with or without use of a base in the reaction of the second step, (15) the type and/or the amount of the base in the reaction of the second step, (16) the reaction temperature in the reaction of the second step, (17) the reaction time in the reaction of the second step, and (18) the type of the compound of the formula (I) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above various reaction conditions are also within the scope of Process 7.
A process for producing a nitroetheneamine of the above formula (I), which comprises reacting a compound represented by the formula (XX): 
xe2x80x83wherein R1, R2, R4, R5 and R6 are as defined above, with a compound represented by the formula (XXI): Xxe2x80x94R3, wherein R3 and X are as defined above.
For the reaction of Process 8, it is preferred to carry out the reaction in the presence of a solvent. The solvent to be specifically used may, for example, be an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroin or petroleum benzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such as acetonitrile or propionitrile; an acid amide such as dimethylformamide or dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amide such as hexamethylphosphoramide; a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and a solvent mixture thereof.
In Process 8, in order to carry out the reaction efficiently, it is preferred to carry out the reaction in the presence of a base. The base to be specifically used may, for example, be an organic base such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkali metal such as lithium, sodium or potassium; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; n-butyl lithium, lithium diisopropylamide or sodium amide.
The reaction of Process 8 is carried out usually at a reaction temperature of from xe2x88x9270 to 150xc2x0 C., preferably at a reaction temperature of from xe2x88x9250 to 100xc2x0 C. The reaction time is usually from 0.1 to 48 hours.
In Process 8, the compound of the formula (XXI) can be used in an amount of from 0.8 to 2 equivalents, preferably from 1 to 1.5 equivalents, per mol of the compound of the above formula (XX).
Various reaction conditions in Process 8 i.e. (1) the type and/or the amount of the compound of the formula (XX), (2) the type and/or the amount of the compound of the formula (XXI), (3) with or without use of a solvent, (4) the type and/or the amount of the solvent, (5) with or without use of a base, (6) the type and/or the amount of the base, (7) the reaction temperature, (8) the reaction time and (9) the type of the compound of the above formula (I) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above various reaction conditions are also in the scope of Process 8.
A compound of the formula (Ixe2x80x3): 
xe2x80x83wherein R1, R4, R5, R6, R8 and R9 are as defined above, is a compound of the above formula (I) and a compound wherein R2 and R3 form together with the N atom a Nxe2x95x90CR8R9 group, wherein R8 and R9 are as defined above. This compound can be produced by a method as shown by the following Process 9.
A process for producing a nitroetheneamine of the above formula (Ixe2x80x3), which comprises reacting a compound represented by the formula (XXII): 
xe2x80x83wherein R1, R4, R5 and R6 are as defined above, with a compound represented by the formula (XXIII): 
xe2x80x83wherein R8 and R9 are as defined above.
For the reaction of Process 9, it is preferred to carry out the reaction in the presence of a solvent. The solvent to be specifically used may, for example, be an alcohol such as methanol, ethanol, propanol or butanol; an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroin or petroleum benzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such as acetonitrile or propionitrile; an acid amide such as dimethylformamide or dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amide such as hexamethylphosphoramide; a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane, and a solvent mixture thereof.
In Process 9, in order to carry out the reaction efficiently, it is preferred to carry out the reaction in the presence of a base. The base to be specifically used may, for example, be an organic base such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; or an alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate.
In Process 9, in order to carry out the reaction efficiently, it is preferred to carry out the reaction in the presence of a dehydrating agent such as molecular sieves. Further, it is also possible to remove formed moisture out of the reaction system by azeotropy using a suitable solvent.
The reaction of Process 9 is carried out usually at a reaction temperature of from xe2x88x9230 to 150xc2x0 C., preferably at a reaction temperature of from 0 to 100xc2x0 C. The reaction time is usually from 0.1 to 48 hours.
In the reaction of Process 9, the compound of the above formula (XXIII) can be used in an amount of from 0.8 to 2 equivalents, preferably from 1 to 1.5 equivalents, per mol of the compound of the above formula (XXII).
Various reaction conditions in Process 9 i.e. (1) the type and/or the amount of the compound of the formula (XXII), (2) the type and/or the amount of the compound of the formula (XXIII), (3) with or without use of a solvent, (4) the type and/or the amount of the solvent, (5) with or without use of a base, (6) the type and/or the amount of the base, (7) with or without use of a dehydrating agent, (8) the type and/or the amount of the dehydrating agent, (9) the reaction temperature, (10) the reaction time, and (11) the type of the compound of the formula (Ixe2x80x3) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above various reaction conditions are also in the scope of Process 9.
A process for producing a nitroetheneamine derivative of the above formula (Ixe2x80x2), which comprises:
(1) a first step of reacting a compound represented by the formula (XXIV): 
xe2x80x83wherein R4 and Z are as defined above, with a compound of the above formula (XVII) to obtain a compound represented by the formula (XXV): 
xe2x80x83wherein R4, R6 and Z are as defined above, and
(2) a second step of reacting the compound of the above formula (XXV) obtained in the first step with a compound of the above formula (V) to obtain a nitroetheneamine derivative of the above formula (Ixe2x80x2).
A process for producing a nitroetheneamine derivative of the after-mentioned formula (Ixe2x80x2xe2x80x3), which comprises:
(1) a first step of reacting a compound represented by the formula (XXVI): 
xe2x80x83wherein R2, R3 and Z are as defined above, with a compound of the above formula (XVII) to obtain a compound of the formula (XXVII): 
xe2x80x83wherein R2, R3, R6 and Z are as defined above, and
(2) a second step of reacting the compound of the above formula (XVII) obtained in the first step with a compound of the above formula (III) to obtain a nitroetheneamine derivative represented by the formula (Ixe2x80x2xe2x80x3): 
xe2x80x83wherein R2, R3, R4, R5 and R6 are as defined above. Here, the compound of the above formula (Ixe2x80x2xe2x80x3) is a compound of the above formula (I) and a compound wherein R1 is a hydrogen atom. Further, the compound of the above formula (XXIV) and the compound of the above formula (XXVI) which are the starting materials in Process 10 and Process 11, can be produced by a known method or a method similar thereto.
The reaction in each step of Process 10 and Process 11 can be carried out in the presence of a suitable solvent. The solvent to be specifically used may, for example, be an alcohol such as methanol, ethanol, propanol or butanol; an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroin or petroleum benzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such as acetonitrile or propionitrile; an acid amide such as dimethylformamide or dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amide such as hexamethylphosphoramide; a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and a solvent mixture thereof.
In Process 10 and Process 11, in order to carry out the reaction of each step efficiently, it is preferred to carry out the reaction in the presence of a base. The base to be specifically used may, for example, be an organic base such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkali metal such as lithium, sodium or potassium; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; or an alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide. Further, in the second step of Process 10, the compound of the above formula (V) acts also as a base. Further, in the second step of Process 11, the compound of the above formula (III) acts also as a base.
Each reaction of the first step in Process 10 and the first step in Process 11 is carried out usually at a reaction temperature of from xe2x88x9230 to 150xc2x0 C., preferably at a reaction temperature of from 0 to 80xc2x0 C. The reaction time is usually from 0.1 to 48 hours. In the first step of Process 10, the compound of the above formula (XVII) can be used in an amount of from 0.8 to 2 equivalents, preferably from 1 to 1.5 equivalents, per mol of the compound of the above formula (XXIV). Further, in the first step of Process 11, the compound of the above formula (XVII) can be used in an amount of from 0.8 to 2 equivalents, preferably from 1 to 1.5 equivalents, per mol of the compound of the above formula (XXVI).
Each reaction of the second step in Process 10 and the second step in Process 11, is carried out usually at a temperature of from xe2x88x9230 to 150xc2x0 C., preferably at a reaction temperature of from 0 to 80xc2x0 C. The reaction time is usually from 0.1 to 48 hours. In the second step of Process 10, the compound of the above formula (V) can be used in an amount of from 1 to 1.5 equivalents, per mol of the compound of the above formula (XXV). Further, in the second step of Process 11, the compound of the above formula (III) can be used in an amount of from 1 to 1.5 equivalents per mol of the compound of the above formula (XXVII).
The compound of the above formula (XXV) obtained in the first step of Process 10 and the compound of the above formula (XXVII) obtained in the first step of Process 11 may be supplied to the respective reactions in the second step of Process 10 and in the second step of Process 11 directly in the form of the reaction mixtures or after separation and purification by a known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization or chromatography.
Various reaction conditions in Process 10 i.e. (1) the type and/or the amount of the compound of the formula (XXIV), (2) the type and/or the amount of the compound of the formula (XVII), (3) with or without use of a solvent in the reaction of the first step, (4) the type and/or the amount of the solvent in the reaction of the first step, (5) with or without use of a base in the reaction of the first step, (6) the type and/or the amount of the base in the reaction of the first step, (7) the reaction temperature of the first step, (8) the reaction time of the first step, (9) the type of the compound of the formula (XXV) which is an intermediate product in the first step, (10) with or without separation and purification of the compound of the above formula (XXV), (11) the type and/or the amount of the compound of the formula (V), (12) with or without use of a solvent in the reaction of the second step, (13) the type and/or the amount of the solvent in the reaction of the second step, (14) with or without use of a base in the reaction of the second step, (15) the type and/or the amount of the base in the reaction of the second step, (16) the reaction temperature in the reaction of the second step, (17) the reaction time in the reaction of the second step, and (18) the type of the compound of the formula (Ixe2x80x2) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above various reaction conditions are also within the scope of Process 10.
Various reaction conditions in Process 11 i.e. (1) the type and/or the amount of the compound of the formula (XXVI), (2) the type and/or the amount of the compound of the formula (XVII), (3) with or without use of a solvent in the reaction of the first step, (4) the type and/or the amount of the solvent in the reaction of the first step, (5) with or without use of a base in the reaction of the first step, (6) the type and/or the amount of the base in the reaction of the first step, (7) the reaction temperature of the first step, (8) the reaction time of the first step, (9) the type of the compound of the formula (XXVII) which is an intermediate product in the first step, (10) with or without separation and purification of the compound of the above formula (XXVII), (11) the type and/or the amount of the compound of the formula (III), (12) with or without use of a solvent in the reaction of the second step, (13) the type and/or the amount of the solvent in the reaction of the second step, (14) with or without use of a base in the reaction of the second step, (15) the type and/or the amount of the base in the reaction of the second step, (16) the reaction temperature in the reaction of the second step, (17) the reaction time in the reaction of the second step, and (18) the type of the compound of the formula (Ixe2x80x2xe2x80x3) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above various reaction conditions are also within the scope of Process 11.
A process for producing a nitroetheneamine derivative of the above formula (Ixe2x80x2), which comprises:
(1) a first step of reacting a compound represented by the above formula (XIII) with a compound of the above formula (XVII) and then reacting a compound of the above formula (XV) to obtain a compound represented by the formula (XXV): 
xe2x80x83wherein R4, R6 and Z are as defined above, and
(2) a second step of reacting the compound of the above formula (XXV) obtained in the first step with a compound of the above formula (V) to obtain a nitroetheneamine derivative of the above formula (Ixe2x80x2).
Each reaction in Process 12 can be carried out in the presence of a suitable solvent. The solvent to be specifically used may, for example, be an alcohol such as methanol, ethanol, propanol or butanol; an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroin or petroleum benzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such as acetonitrile or propionitrile; an acid amide such as dimethylformamide or dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amide such as hexamethylphosphoramide; a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and a solvent mixture thereof.
In Process 12, in order to carry out each reaction efficiently, it is preferred to carry out the reaction in the presence of a base. The base to be specifically used may, for example, be an organic base such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkali metal such as lithium, sodium or potassium; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate; an alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; or an alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide. Further, in the second step of Process 12, the compound of the above formula (V) acts also as a base.
The reaction in the first step of Process 12 is carried out usually at a reaction temperature of from xe2x88x9230 to 150xc2x0 C., preferably at a reaction temperature of from 0 to 80xc2x0 C. The reaction time is usually from 0.1 to 48 hours.
In the first step of Process 12, the compounds of the above formula (XVII) and the formula (XV) can be used in an amount of from 0.8 to 2 equivalents, preferably from 1 to 1.5 equivalents, per mol of the compound of the above formula (XIII), respectively.
The compound of the above formula (XXV) obtained in the first step of Process 12 may be supplied to the reaction of the second step of Process 12 directly in the form of the reaction mixture or after separation and purification by a known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization or chromatography.
The reaction of the second step of Process 12 is carried out usually at a reaction temperature of from xe2x88x9230 to 150xc2x0 C., preferably at a reaction temperature of from 0 to 80xc2x0 C. The reaction time is usually from 0.1 to 48 hours.
In the second step of Process 12, the compound of the above formula (V) can be used in an amount of from 1 to 1.5 equivalents per mol of the compound of the above formula (XXV).
Various reaction conditions in Process 12 i.e. (1) the type and/or the amount of the compound of the formula (XIII), (2) the type and/or the amount of the compound of the formula (XVII), (3) the type and/or the amount of the compound of the formula (XV), (4) with or without use of a solvent in the reaction of the first step, (5) the type and/or the amount of the solvent in the reaction of the first step, (6) with a without use of a base in the reaction of the first step, (7) the type and/or the amount of the base in the reaction of the first step, (8) the reaction temperature of the first step, (9) the reaction time of the first step, (10) the type of the compound of the formula (XXV) which is an intermediate product in the first step, (11) with or without separation and purification of the compound of the above formula (XXV), (12) the type and/or the amount of the compound of the formula (V), (13) with or without use of a solvent in the reaction of the second step, (14) the type and/or the amount of the solvent in the reaction of the second step, (15) with or without use of a base in the reaction of the second step, (16) the type and/or the amount of the base in the reaction of the second step, (17) the reaction temperature in the reaction of the second step, (18) the reaction time in the reaction of the second step, and (19) the type of the compound of the formula (Ixe2x80x2) as the final desired product, may mutually suitably be combined. Further, among these various reaction conditions, there are some which have a reaction condition of a usual range and a reaction condition of a preferred range, and they may also mutually suitably be selected and combined.
Combinations of the above various reaction conditions are also within the scope of Process 12.
The compounds of the above formula (I) (inclusive of compounds of the formula (Ixe2x80x2), the formula (Ixe2x80x3) and the formula (Ixe2x80x2xe2x80x3)) obtained by the processes as described in the foregoing Processes 1 to 12, can be isolated and purified by a known means such as concentration, concentration under reduced pressure, distillation, fractionation, redistribution, solvent extraction, crystallization, recrystallization or chromatography.
When the compound of the above formula (I) is obtained in a free form, it may be formed into a salt by a usual method. Further, the compound of the above formula (I) may form an intramolecular salt. The compounds of the above formula (I), and their stereoisomers or tautomer exhibit matrix metalloproteinase inhibition activities individually or in a state of a mixture. The production flowcharts of the above-described Processes 1 to 12 will be shown below. 
Now, specific Preparation Examples for nitroetheneamine derivatives of the above formula (I) and the intermediates for their production, will be described including specific embodiments of the processes for the production of nitroetheneamine derivatives represented by the above formula (I).
250 mg of N-methyl-1-hydrazino-2-nitroetheneamine, 210 mg of 2-pyridinecarbaldehyde and 5 ml of ethanol were stirred for about 30 minutes under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with a small amount of ethanol and then dried to obtain 300 mg of 2-pyridinecarbaldehyde 1-methylamino-2-nitroethenylhydrazone (Compound No. 29) having a melting of 165xc2x0 C. (decomposed).
500 mg of N-methyl-1-methylthio-2-nitroetheneamine, 770 mg of 1-methyl-1-(3-chloro-5-trifluoromethyl-2-pyridyl)hydrazine and 7 ml of 1,4-dioxane were stirred for about 4 hours under heating and refluxing and then cooled to room temperature, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain 370 mg of N-methyl-1-(2-methyl-2-(3-chloro-5-trifluoromethyl-2-pyridyl)hydrazino)-2-nitroetheneamine (Compound No. 35) having a melting point of from 159 to 160xc2x0 C. (decomposed).
(1) 9 g of a 28% sodium methylate methanol solution was dissolved in 30 ml of methanol, and a solution obtained by dissolving 10 g of 2,6-dichloro-4-trifluoromethylpyridine in 15 ml of methanol, was dropwise added thereto, followed by stirring for about 90 minutes under heating and refluxing. After completion of the reaction, the solution was cooled to room temperature, and about 40 ml of an ether was added, whereupon an insoluble substance was removed by filtration, and then the filtrate was concentrated under reduced pressure. To the concentrated residue, 15 ml of n-propanol and 6 g of hydrazine monohydrate were added, followed by stirring for about 19 hours under heating and refluxing. After completion of the reaction, the solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The concentrated residue was extracted with chloroform and dried over anhydrous sodium sulfate, whereupon the solvent was distilled off under reduced pressure to obtain 6.6 g of crude 4-trifluoromethyl-6-methoxy-2-pyridylhydrazine (Intermediate No. 71).
(2) 4.7 g of N-methyl-1-methylthio-2-nitroetheneamine, 6.6 g of crude 4-trifluoromethyl-6-methoxy-2-pyridylhydrazine (Intermediate No. 71) and 35 ml of ethanol were stirred for about 5.5 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with a small amount of methanol and then dried to obtain 2.7 g of N-methyl-1-(2-(4-trifluoromethyl-6-methoxy-2-pyridyl)hydrazino)-2-nitroetheneamine (Compound No. 98) having a melting point of 193xc2x0 C. (decomposed).
(1) 3.00 g of 1,1-bis(methylthio)-2-nitroethene, 3.38 g of 4-trifluoromethoxyaniline and 30 ml of ethanol were reacted for 5 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration and washed with a small amount of ethanol and dried to obtain 3.40 g of crystals, to which 1.81 g of 4-trifluoromethoxyaniline and 30 ml of ethanol were added and reacted for 6.5 hours under heating and refluxing. After completion of the reaction, the solution was cooled to room temperature, and precipitated crystals were collected by filtration, washed with a small amount of ethanol and dried to obtain 2.51 g of N-(1-methylthio-2-nitroethenyl)-4-trifluoromethoxyaniline (Intermediate No. 30) having a melting point of from 114 to 115xc2x0 C.
(2) To 2.00 g of N-(1-methylthio-2-nitroethenyl)-4-trifluoromethoxyaniline (Intermediate No. 30) obtained in the above step (1), 40 ml of ethanol was added at room temperature, and then 0.36 g of hydrazine monohydrate was dropwise added thereto. Thereafter, the reaction was carried out for 1 hour under heating and refluxing. After completion of the reaction, the solution was cooled to room temperature, and precipitated crystals were collected by filtration, washed with a small amount of ethanol and dried to obtain 1.36 g of the desired product (Compound No. 61) having a melting point of 161xc2x0 C. (decomposition point).
(1) In 20 ml of dimethylsulfoxide, 2.00 g of N-((bismethylthio)methylene)methanesulfonamide, 0.92 g of nitromethane and 2.27 g of potassium carbonate were added and reacted for 6 hours at room temperature. The reaction mixture was poured into 75 ml of ice water and then acidified (pH=3) with 6N hydrochloric acid, whereupon precipitated crystals were collected by filtration, washed with a small amount of water and dried to obtain 0.49 g of N-(1-(methylthio)-2-nitroethenyl)methanesulfonamide (Intermediate No. 57) having a melting point of from 81 to 82xc2x0 C.
(2) 0.40 g of N-(1-(methylthio)-2-nitroethenyl)methanesulfonamide (Intermediate No. 57) obtained in the above step (1), 0.40 g of 6-chloro-4-trifluoromethyl-2-pyridylhydrazine and 10 ml of ethanol were stirred for 1.5 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with a small amount of ethanol and then dried to obtain 0.37 g of N-(1-(6-chloro-4-trifluoromethyl-2-pyridyl)hydrazino-2-nitroethenyl)methanesulfonamide (Compound No. 157) having a melting point of 190xc2x0 C. (decomposed).
1.40 g of N-(1-(methylthio)-2-nitroethenyl)methanesulfonamide (Intermediate No. 57), 1.80 g of 6-(2-ethoxyethoxy)-4-trifluoromethyl-2-pyridylhydrazine and 11 ml of ethanol were stirred for 15 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with a small amount of ethanol and then dried to obtain 0.97 g of N-(1-(6-(2-ethoxyethoxy)-4-trifluoromethyl-2-pyridyl)hydrazino-2-nitroethenyl)methanesulfonamide (Compound No. 164) having a melting point of 153xc2x0 C.
(1) 0.32 ml of nitromethane, 0.24 g of sodium hydride and 20 ml of N,N-dimethylformamide were stirred for 1 hour in a nitrogen atmosphere, and then 1.57 g of N-((bismethylthio)methylene)benzenesulfonamide was added thereto and reacted for 22 hours at room temperature. The reaction mixture was poured into 200 ml of ice water, and n-hexane was added and stirred for 30 minutes, followed by liquid separation to remove an organic layer. The aqueous layer was acidified (pH=3) with 6N hydrochloric acid, and then the oil content was extracted with an ether. The obtained extract solution was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.27 g of oily N-(1-(methylthio)-2-nitroethenyl)benzenesulfonamide (Intermediate No. 56).
(2) 0.27 g of N-(1-(methylthio)-2-nitroethenyl)benzenesulfonamide (Intermediate No. 56) obtained in the above step (1), 0.10 g of N-aminomorpholine and 4 ml of ethanol were stirred for 24 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with a small amount of ethanol/n-hexane mixed liquid (1/1) and then dried to obtain 0.22 g of N-(1-(N-morpholino)amino-2-nitroethenyl)methanesulfonamide (Compound No. 163) having a melting point of from 127 to 130xc2x0 C.
Preparation Examples of compounds of the above formula (I) prepared by the methods of Preparation Examples 1 to 7 and in accordance with the above-described Processes 1 to 12, are shown in the following Tables 1 to 23.
Preparation Examples of compounds of the above formula (IV) which are intermediates for the preparation of compounds of the above formula (I) prepared by a process in accordance with the above-described Process 1-1, are shown in the following Tables 24 to 29.
Among the compounds of the above formula (V) as intermediates to be used for the above Processes 1, 2 and 4, compounds represented by the formula (Vxe2x80x2): 
wherein R is as defined below, which are compounds wherein Y, R1 and R3 is a hydrogen atom, and R2 is: 
wherein R is a halogen atom (provided that a chlorine atom is excluded) or an organic group (provided that a trifluoromethyl group, a methyl group, a phenyl group and a thienyl group are excluded), are novel compounds and can be prepared by a method in accordance with above Preparation Example 3(1). Specific Preparation Examples thereof are shown in Tables 30 to 33.
Nitroetheneamine derivatives represented by the above formula (I) or salts thereof have matrix metalloproteinase inhibition activities, particularly MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9 inhibition activities. Among them, MMP-3- and MMP-9 inhibition activities are particularly excellent, and MMP-9 inhibition activities are the best. Not only the compounds of the above formula (I) and salts thereof, compounds of the above formula (IV) or salts thereof, which are intermediates for the preparation of the compounds of the above formula (I) have the above-described matrix metalloproteinase inhibition activities. Accordingly, by using them as active constituents and by combining the after-mentioned carrier, etc., as the case requires, matrix metalloproteinase inhibitors of the present invention can be provided. Further, a medical composition will be provided which comprises a therapeutically effective amount of the compound of the above formula (I) or a salt thereof, or the compound of the above formula (IV) or a salt thereof and a pharmaceutically acceptable carrier. To apply the pharmaceutical composition of the present invention to clinical treatment as an angiogenesis inhibitor, an anticancer agent, a tumor cell infiltration inhibitor or a tumor metastatis inhibitor to be used for treatment or prevention of a cancer or inflammatory diseases or as a therapeutic or preventive agent for rheumatoid arthritis, it is preferred to make it a formulation having an additive such as a diluent, an excipient or a stabilizer further incorporated as the case requires to the medical composition comprising the above active constituent and the pharmaceutical acceptable carrier.
In the medical composition of the present invention, the blend proportion of the above active constituent to the carrier component is usually from 1.0 to 90% w/w. The dosage effective for treatment is usually from 0.1 to 1000 mg/day/person in the case of an adult, although it varies depending upon e.g. the administration method, the sex, the weight and the age of the patient and the disease to be treated.
With respect to the formulation and the administration mode, it may be orally administered in the form of a formulation such as a granule, a loose granule or a pilula, a tablet, a capsule or a solution or in the form of a bulk powder, or it may be administered by non-oral route in the form of a suppository, an aerosol or formulation for local administration such as collunarium. As an injection solution, it may be administered by intravenous administration, intramuscular administration, subcutaneous administration or articular cavity administration. Further, it may be prepared in the form of a powder for injection and may be formulated at the time of use.
A pharmaceutical, organic or inorganic, solid or liquid carrier or diluent suitable for oral, enteral or perenteral administration can be used for formulating the medical composition of the present invention. A typical carrier or diluent which can be incorporated to tablets or capsules, may be a disintegrant such as Acacia, corn starch or alginic acid, a lubricant such as magnesium stearate or a sweetener such as saccharose or lactose. When the formulation is capsules, in addition to the above substance, a liquid carrier such as fatty oil may be incorporated. Various other substances can be used as a coating agent or a physical shape improving agent for a dosage unit. For example, it is preferred to dissolve or suspend the active ingredient in water or in an excipient such as natural vegetable oil or in a synthetic fatty excipient such as ethyl oleate. A buffer agent such as a citrate, an acetate or a phosphate, or an anti oxidant such as ascorbic acid, may also be incorporated in accordance with an acceptable medical method.